BACKGROUND: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). METHODS: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. RESULTS: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). CONCLUSIONS: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Adult Cancer Program Lowy Cancer Research Centre University of NSW Sydney Sydney New South Wales Australia

Aix Marseille Université INSERM IRD SESSTIM Marseille France

AnaNeo Therapeutics New York NY USA

Assuta Medical Center Tel Aviv Israel

Basser Center for BRCA Abramson Cancer Center University of Pennsylvania Philadelphia PA USA

BMC Faculty of Medicine University of Iceland Reykjavik Iceland

British Columbia's Ovarian Cancer Research Program BC Cancer Vancouver General Hospital and University of British Columbia Vancouver BC Canada

Cancer Epidemiology Division Cancer Council Victoria East Melbourne Victoria Australia

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Genetics and Prevention Program University of California San Francisco San Francisco CA USA

Cancer Genetics Group IPO Porto Research Center Porto Comprehensive Cancer Center Porto Portugal

Cancer Genetics Laboratory Peter MacCallum Cancer Centre Melbourne Victoria Australia

Cancer Prevention and Control Program Rutgers Cancer Institute of New Jersey New Brunswick NJ USA

Cancer Registry of Norway Norwegian Institute of Public Health Oslo Norway

Cancer Research Institute Ghent Ghent Belgium

Cancer Research UK Cambridge Institute University of Cambridge Cambridge UK

Carmel Medical Center Haifa Israel

Center for Bioinformatics and Functional Genomics Cedars Sinai Medical Center Los Angeles CA USA

Center for Clinical Cancer Genetics The University of Chicago Chicago IL USA

Center for Familial Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Integrated Oncology Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Center for Medical Genetics NorthShore University HealthSystem Evanston IL USA

Centre for Cancer Biomarkers CCBIO Department of Clinical Science University of Bergen Bergen Norway

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Melbourne Victoria Australia

Centre for Medical Genetics Ghent University Gent Belgium

Centro de Investigación en Red de Enfermedades Raras Madrid Spain

Chronic Disease Epidemiology Yale School of Medicine New Haven CT USA

City of Hope Clinical Cancer Genetics Community Research Network Duarte CA USA

Clinical Cancer Epidemiology Institute of Cancer Research London UK

Clinical Cancer Genomics City of Hope Duarte CA USA

Clinical Cancer Research Center Aalborg University Hospital Aalborg Denmark

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London UK

Clinical Genetics Research Lab Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York NY USA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Clinical Genome Center Department of Clinical Research University of Southern Denmark Odense Denmark

David Geffen School of Medicine Department of Obstetrics and Gynecology University of California at Los Angeles Los Angeles CA USA

Département d'Anticipation et de Suivi des Cancers Oncogénétique Clinique Institut Paoli Calmettes Marseille France

Département de Biopathologie Centre François Baclesse Caen France

Department of Basic Sciences Shaukat Khanum Memorial Cancer Hospital and Research Centre Lahore Pakistan

Department of Biomedical Data Science Stanford University School of Medicine Stanford CA USA

Department of Biomolecular Medicine University of Ghent Ghent Belgium

Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Cancer Biology and Genetics The Ohio State University Columbus OH USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Cancer Epidemiology Moffitt Cancer Center Tampa FL USA

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia PA USA

Department of Clinical Genetics Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Medicine Aalborg University Aalborg Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Clinical Pathology Melbourne Medical School University of Melbourne Parkville Victoria Australia

Department of Computational Biomedicine Cedars Sinai Medical Center Los Angeles CA USA

Department of Epidemiology and Population Sciences Stanford University School of Medicine Stanford University Stanford CA USA

Department of Epidemiology Colorado School of Public Health University of Colorado Aurora CO USA

Department of Epidemiology Genetic Epidemiology Research Institute University of California Irvine Irvine CA USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology University of Michigan School of Public Health Ann Arbor MI USA

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Experimental and Clinical Biomedical Sciences 'Mario Serio' Medical Genetics Unit University of Florence Florence Italy

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Gynaecological Oncology Westmead Hospital Sydney New South Wales Australia

Department of Gynecologic Oncology Duke University Hospital Durham NC USA

Department of Gynecology and Gynecologic Oncology Kliniken Essen Mitte Essen Germany

Department of Health Science and Policy Icahn School of Medicine at Mount Sinai New York NY USA

Department of Human and Medical Genetics Faculty of Medicine Vilnius University Vilnius Lithuania

Department of Internal Medicine Division of Human Genetics The Ohio State University Columbus OH USA

Department of Internal Medicine Division of Medical Oncology University of Kansas Medical Center Westwood KS USA

Department of Internal Medicine Huntsman Cancer Institute University of Utah Health Salt Lake City UT USA

Department of Laboratory Genetics Portuguese Oncology Institute of Porto Porto Comprehensive Cancer Center Porto Portugal

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge UK

Department of Medical Oncology Family Cancer Clinic Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Medical Oncology University Hospital of Vall d'Hebron Barcelona Spain

Department of Medicine Huntsman Cancer Institute University of Utah Health Salt Lake City UT USA

Department of Medicine Stanford University School of Medicine Stanford University Stanford CA USA

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto ON Canada

Department of Molecular Medicine Faculty of Medicine Université Laval Québec City QC Canada

Department of Molecular Oncology BC Cancer Research Centre Vancouver BC Canada

Department of Obstetrics and Gynecology Brigham and Women's Hospital Boston MA USA

Department of Obstetrics and Gynecology Haukeland University Hospital Bergen Norway

Department of Obstetrics and Gynecology Providence Medical Center Medford OR USA

Department of Obstetrics and Gynecology University of British Columbia Vancouver BC Canada

Department of Obstetrics and Gynecology Vanderbilt University Medical Center Nashville TN USA

Department of Obstetrics Gynecology and Reproductive Biology Harvard Medical School Boston MA USA

Department of Oncology Biobank National Institute of Oncology Budapest Hungary

Department of Oncology Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Oncology Mayo Clinic Rochester MN USA

Department of Pathology and Laboratory Medicine Institute of Oncology and Maria Sklodowska Curie Cancer Center Warsaw Poland

Department of Pathology and Laboratory Medicine University of British Columbia Vancouver BC Canada

Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City KS USA

Department of Pathology and Molecular Immunology School of Medicine and Biomedical Sciences University of Porto Porto Portugal

Department of Pathology Landspitali the National University Hospital of Iceland Reykjavik Iceland

Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Population and Public Health Sciences University of Southern California Los Angeles CA USA

Department of Population Sciences Beckman Research Institute of City of Hope Duarte CA USA

Department of Preventive Medicine Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center Los Angeles CA USA

Department of Public Health Sciences University of Virginia Charlottesville VA USA

Department of Quantitative Health Sciences Mayo Clinic College of Medicine Rochester MN USA

Department of Radiation Oncology Hannover Medical School Hannover Germany

Department of Tumor Growth Biology N N Petrov Institute of Oncology St Petersburg Russia

Dept of OB GYN and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Division of Cancer and Ovarian Cancer Action Research Centre Department Surgery and Cancer Imperial College London London UK

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Cancer Prevention and Genetics IEO European Institute of Oncology IRCCS Milan Italy

Division of Gynecologic Oncology Department of Obstetrics and Gynecology Women's Cancer Program at the Samuel Oschin Cancer Institute Cedars Sinai Medical Center Los Angeles CA USA

Division of Gynecologic Oncology Department of Obstetrics Gynecology and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh PA USA

Division of Gynecologic Oncology University Hospital Leuven Leuven Belgium

Epidemiology Branch National Institute of Environmental Health Sciences NIH Rockville MD USA

Escola de Doutoramento Internacional Universidade de Santiago Santiago de Compostela Spain

Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia

Familial Cancer Clinical Unit Human Cancer Genetics Programme Madrid Spain

Family Cancer Clinic The Netherlands Cancer Institute Antoni van Leeuwenhoek hospital Amsterdam The Netherlands

Fundación Pública Galega de Medicina Xenómica Santiago de Compostela Spain

Genetics Department Institut Curie Paris France

Genome Diagnostics Program IFOM the FIRC Institute of Molecular Oncology Milan Italy

Genomic Medicine Division of Evolution and Genomic Sciences The University of Manchester Manchester Academic Health Science Centre Manchester Universities Foundation Trust St Mary's Hospital Manchester UK

Genomic Medicine North West Genomics hub Manchester Academic Health Science Centre Manchester Universities Foundation Trust St Mary's Hospital Manchester UK

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center Québec City QC Canada

Gynaecology Research Unit Hannover Medical School Hannover Germany

Health Informatics Institute Morsani College of Medicine University of South Florida Tampa FL USA

Hematology Oncology and Transfusion Medicine Center Oncogenetics Unit Vilnius University Hospital Santaros Clinics Vilnius Lithuania

Hereditary Cancer Genetics Group Vall d'Hebron Institute of Oncology Barcelona Spain

Hereditary Cancer Program IDIBELL Catalan Institute of Oncology Barcelona Spain

Hereditary Cancer Program Kaiser Permanente Northern California San Francisco CA USA

Human Genotyping Unit CeGen Spanish National Cancer Research Centre Madrid Spain

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua Italy

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin Poland

Inserm U900 Paris France

Institut Curie Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute of Cancer Sciences University of Glasgow Glasgow UK

Institute of Human Genetics University Hospital Heidelberg Heidelberg Germany

Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain

Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research Georgetown University Washington DC USA

Leuven Cancer Institute University of Leuven Leuven Belgium

Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Canada

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA

Medical Birth Registry of Norway Norwegian Institute of Public Health Norway

Medical Genetics Unit St George's University of London London UK

Mines ParisTech Fontainebleau France

Molecular Diagnostics Aalborg University Hospital Aalborg Denmark

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research 'Demokritos' Athens Greece

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

Molecular Oncology Laboratory CIBERONC Hospital Clinico San Carlos IdISSC Madrid Spain

MRC Clinical Trials Unit at UCL Institute of Clinical Trials and Methodology University College London London UK

MRC Integrative Epidemiology Unit University of Bristol Bristol UK

N N Alexandrov Research Institute of Oncology and Medical Radiology Minsk Belarus

National Cancer Institute Clinical Genetics Branch Division of Cancer Epidemiology and Genetics Bethesda MD USA

National Tumour Biology Laboratory National Institute of Oncology Budapest Hungary

Obstetrics and Gynecology Epidemiology Center Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Parkville Familial Cancer Centre Peter MacCallum Cancer Center and the Royal Melbourne Hospital Melbourne Victoria Australia

Population Health Program QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

Princess Margaret Cancer Center Toronto Canada

ProCURE IDIBELL Catalan Institute of Oncology Barcelona Spain

ProCURE IDIBGI Catalan Institute of Oncology Girona Spain

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal QC Canada

Program in Epidemiology Division of Public Health Sciences Fred Hutchinson Cancer Center Seattle WA USA

Providence Cancer Center Medford OR USA

PSL Research University Paris France

Radboud Institute for Health Sciences Radboud University Medical Center Nijmegen The Netherlands

Roswell Park Comprehensive Cancer Center Buffalo NY USA

Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel

Samuel Oschin Comprehensive Cancer Institute Cancer Prevention and Genetics Program Cedars Sinai Medical Center Los Angeles CA USA

School of Clinical Medicine Faculty of Medicine and Health University of NSW Sydney Sydney New South Wales Australia

Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Centre UCLA Los Angeles CA USA

Sir Peter MacCallum Department of Oncology University of Melbourne Melbourne Victoria Australia

SOD Genetica Molecolare University Hospital Pisa Italy

Spanish Network on Rare Diseases Madrid Spain

Stanford Cancer Institute Stanford University School of Medicine Stanford University Stanford CA USA

State Research Institute Centre for Innovative Medicine Vilnius Lithuania

Technion Israel Institute of Technology Haifa Israel

The Association for Promotion of Research in Precision Medicine Haifa Israel

The Daffodil Centre The University of Sydney a joint venture with Cancer Council NSW Sydney New South Wales Australia

The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center Ramat Gan Israel

The University of Chicago Pritzker School of Medicine Chicago IL USA

Ufa University of Science and Technology Ufa Russia

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Unité INSERM U830 Paris France

Université Paris Cité Paris France

University Medical Center Groningen Department of Genetics University of Groningen Groningen The Netherlands

Veneto Institute of Oncology IOV IRCSS Italy

Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA USA

Womens Cancer Research Center Magee Womens Research Institute and Hillman Cancer Center Pittsburgh PA USA

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